The present invention relates to methods of treating disorders related to cellular overproliferation comprising neutralizing the production or activity of macrophage migration inhibitory factor (MIF). The invention also relates to therapeutic compositions comprising factors which inhibit or neutralize MIF activity, such as, MIF antisense RNA molecules and MIF monoclonal antibodies and derivatives or analogs thereof. The invention further relates to the uses of such compositions and methods for the treatment of malignancies, including, but not limited to, B and T cell lymphomas.
MIF was the first lymphokine to be discovered and was originally identified by its ability to prevent the migration of guinea pig macrophages in vitro (Bloom and Bennett, 1966, Science 153:80-82; David, 1966, Proc. Natl. Acad. Sci. USA 56:72-77). Given this activity, the role of MIF activity in inflammation and the immune system was investigated, however the precise role of MIF in either local or systemic inflammatory responses has remained largely undefined. Likewise the role of MIF in other physiological and pathophysiological is still enigmatic.
MIF has been reported to be associated with delayed-type hypersensitivity reactions (Bloom and Bennett, 1966, supra; David, 1966, supra), to be produced by lectin-activated T-cells (Weiser et al., 1981, J. Immunol. 126: 1958-1962), and to enhance macrophage adherence, phagocytosis and tumoricidal activity (Nathan et al., 1973, J. Exp. Med. 137: 275-288; Nathan et al., 1971, J. Exp. Med. 133: 1356-1376; Churchill et al., 1975, J. Immunol. 115: 781-785). Unfortunately, many of these studies used mixed culture supernatants that were shown later to contain other cytokines, such as IFN-xcex3 and IL-4, that also have migration inhibitory activity (McInnes and Rennick, 1988, J. Exp. Med. 167: 598-611; Thurman et al., 1985, J. Immunol. 134: 305-309).
Recombinant human MIF was originally cloned from a human T cell library (Weiser et al., 1989, Proc. Natl. Acad. Sci. USA 86: 7522-7526), and has been shown to activate blood-derived macrophages to kill intracellular parasites and tumor cells in vitro, to stimulate IL-1xcex2 and TNFxcex1 expression, and to induce nitric oxide synthesis (Weiser et al., 1991, J. Immunol. 147: 2006-2011; Pozzi et al., 1992, Cellular Immunol. 145: 372-379; Weiser et al., 1992, Proc. Natl. Acad. Sci. USA 89:8049-8052; Cunha et al., 1993, J. Immunol. 150:1908-1912). Until very recently, however, the lack of a reliable source of purified MIF has continued to hamper investigation of the precise biological profile of this molecule.
The present invention relates to methods of treating disorders related to cellular overproliferation by neutralizing the activity of MIF. In particular, the present invention relates to the treatment of such disorders by suppressing the production or neutralizing the activity of MIF with anti-MIF monoclonal antibodies or suppressing MIF production with MIF antisense RNA molecules. The invention encompasses therapeutic compositions comprising MIF monoclonal antibodies and derivatives and analogs thereof. The invention further encompasses therapeutic compositions comprising MIF antisense RNA molecules and derivatives and analogs thereof.
The invention relates to the uses of therapeutic compositions which inhibit the production or activity of MIF for the treatment or prevention of tumor related disorders. In a specific embodiment of the invention, therapeutic compositions comprising neutralizing MIF monoclonal antibodies are used to treat B and T cell lymphomas.
The invention is based, in part, on the Applicants"" unexpected finding that MIF is required for the proliferation of T cells in vitro. Neutralizing monoclonal antibodies (mAbs) against MIF directly inhibited the proliferation of anti-CD3 induced primary T cells. These results suggest that MIF functions as a cellular growth factor and that MIF plays a role in regulating cellular proliferation.
The invention is further based on the Applicants"" surprising discovery that the administration of neutralizing monoclonal antibodies to MIF inhibits the growth of tumors in a murine B cell lymphoma model. These observations indicate an unexpected involvement of MIF in regulating cell cycle and cell growth in vivo at the organismal level. These results suggest that neutralizing the activity of MIF has significant antitumor activity. In addition, the invention is based on the Applicant""s discovery that anti-MIF factors inhibit cellular factors required for tumor establishment, such as, the establishment of tumor neovascularization.
The invention is illustrated by working examples which, among other things, demonstrate that MIF monoclonal antibodies have significant antitumor activity in vivo in a murine B cell lymphoma model.